Phenotypic variability within the JAK2 V617F-positive MPD: Roles of progenitor cell and neutrophil allele burdens

Objective: The myeloproliferative disorders (MPD), polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF), differ phenotypically, but share the same JAK2^V617F mutation. We examined the relationship of the quantitative JAK2^V617F allele burden to MPD disease phenotype among the three MPD classes and within PV. Materials and Methods: We measured the JAK2^V617F allele percentage in genomic DNA from neutrophils, CD34⁺ cells, and cloned progenitors in 212 JAK2^V617F-positive MPD patients and correlated the allele burdens to both disease class and disease features. Results: In ET and PV, mean CD34⁺ cell JAK2^V617F allele burdens were lower than the corresponding neutrophil allele burdens, but these were equivalent in PMF. JAK2^WT progenitors were present in ET and PV when the CD34⁺ JAK2^V617F allele burden was lower than the neutrophil allele burden, but not in PV and PMF subjects in whom the CD34⁺ cell and neutrophil allele burdens were similar. CD34⁺ cell JAK2^V617F clonal dominance, defined as coherence between the CD34⁺ cell and neutrophil JAK2^V617F allele burdens, was present in 24% of ET, 56% of PV, and 93% of PMF patients, and was independent of the CD34⁺ cell JAK2^V617F genotype. Clonally dominant PV patients had significantly longer disease durations, higher white cell counts, and larger spleens than nondominant PV patients. Conclusions: We conclude that the extent of JAK2^V617F CD34⁺ cell clonal dominance is associated with disease phenotype within the MPD and, in PV, is associated with extramedullary disease, leukocytosis, and disease duration.